Previous studies have emphasized that after brain and spinal cord injury there are dramatic reductions in levels of the second messenger cyclic adenosine monophosphate (cAMP), a critical intracellular signaling molecule in neurons and inflammatory cells. Over the last funding period, our laboratory has found that after traumatic brain injury (TBI) cAMP reductions participate in the vulnerability of the posttraumatic brain to secondary injuries such as hemodynamic alterations, inflammation, and long-term synaptic dysfunction. Phosphodiesterase 4 (PDE4) is the major enzyme responsible for cAMP hydrolysis in the brain and currently is an important molecular target for the treatment of various human neurological diseases including neurotrauma. Studies we have completed during the previous funding period have emphasized the complexity of the response to trauma of different PDE4 isoforms in terms of their various time-dependent cellular responses. The characterization of these cellular and biochemical changes are critical for the development and testing of new inhibitors against specific PDE4 isoforms. In the current proposal, we will address several knowledge gaps that hamper clinical development of PDE4 inhibitors for the treatment of TBI, including the identification of PDE4 isoforms in specific inflammatory cell populations as well as assessing the effects on isoform-selective PDE4 inhibitors on posttraumatic inflammation. Another exciting recent discovery that will be investigated is the ability of PDE4B isoform-specific inhibitors to significantly reduce chronic cognitive deficits, thereby providing a novel therapeutic strategy for people living with TBI. Based on our previous and new preliminary data, we therefore propose the following four aims: 1) To investigate the contribution of PDE4B to acute inflammation after TBI, 2) To determine if inhibition of PDE4B acutely after TBI improves pathology and behavioral outcome, 3) To test whether a PDE4B isoform-selective inhibitor improves chronic cognitive deficits, and finally, 4) To directly determine if loss of PDE4B improves outcome and loss of PDE4D worsens outcome after TBI. These studies will determine which specific PDE4 isoforms need to be selectively inhibited at different therapeutic time windows after TBI to reduce inflammation and pathology, and promote recovery in three therapeutic time windows, acute, subacute and chronic. Together, these studies will provide critical information regarding the precise cellular events by which isoform-selective PDE4 inhibitors produce their benefits, and provide evidence-based mechanistic data to support the use of PDE4 inhibitors in acute, subacute, and chronic therapeutic time windows after TBI. This proposal is supported by a multidisciplinary, multi-institutional research team with experience in experimental TBI models, PDE4B and PDE4D knockout mice, and a pharmacological partner with an established record in CNS drug discovery. These studies will provide the necessary preclinical data for the clinical translation of these novel agents for the treatment of TBI.